TNF Inhibitor Formulation Viscosity Control for Implantable Infusion
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Solution Overview
Problem
Developing stable and compatible formulations for tumor necrosis factor (TNF) inhibitors for use in implantable infusion devices is challenging due to the tendency of large molecules to agglomerate and increase viscosity, which can lead to issues with proper flow and wear on the pumping mechanism.
Innovation Solution
The development of injectable formulations containing TNF inhibitors, specifically dominant-negative TNF inhibitors, with a concentration of 5 mg/ml to 500 mg/ml, a phosphate or citrate buffer, an ionic strength of 0.1-0.2 M, 5-10% carbohydrate, pH between 6 and 7, and viscosity of less than 10 centipoise, ensuring stability and compatibility with implantable infusion devices.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If TNF inhibitor polypeptide concentration is increased to improve therapeutic efficacy, then treatment effectiveness improves, but viscosity increases and flow properties deteriorate
Solution Approach 1:
The patent applies parameter changes by optimizing the pH of the formulation to between 6.0 and 7.0, which prevents polypeptide aggregation and maintains low viscosity even at high concentrations (5-500 mg/ml). This pH optimization allows the formulation to achieve both high therapeutic dosage and good flow properties for implantable device delivery
Solution Approach 2:
The patent uses composite formulation components including phosphate or citrate buffers combined with specific carbohydrates (5-10% w/v) to create a stable formulation. This composite approach maintains polypeptide solubility and prevents aggregation, enabling high concentration delivery without compromising flow characteristics
2Volume of stationary object
If TNF inhibitor concentration is increased to reduce device reservoir volume, then device size decreases, but viscosity increases and pumping becomes difficult
Solution Approach 1:
By changing the pH parameter to the optimized range of 6.0-7.0 and controlling ionic strength, the formulation maintains viscosity below 10 centipoise at high polypeptide concentrations. This enables concentration of 5-500 mg/ml in small reservoir volumes while preserving pumping capability through appropriate catheter and pump selection
3Ease of operation
If formulation viscosity is reduced to improve flow and pumping, then deliverability improves, but polypeptide stability may be compromised
Solution Approach 1:
The patent optimizes pH to 6.0-7.0 and controls ionic strength to maintain viscosity below 10 centipoise while simultaneously preventing polypeptide aggregation and degradation. This parameter optimization achieves both low viscosity for easy deliverability and high stability for chronic storage and infusion
Solution Approach 2:
The formulation combines phosphate or citrate buffers with carbohydrates at 5-10% w/v concentration to create a composite system that provides both low viscosity and high polypeptide stability. The carbohydrate components prevent aggregation while the buffer system maintains optimal pH, achieving both deliverability and stability requirements
4Object-affected harmful factors
If implantable infusion device is used for targeted delivery to reduce side effects, then therapeutic index improves, but formulation requirements become more stringent
Solution Approach 1:
The patent specifies precise parameter ranges (pH 6.0-7.0, viscosity <10 cP, ionic strength equivalent to 0.1-0.2 M NaCl, carbohydrate 5-10% w/v) to ensure compatibility with implantable infusion devices. These controlled parameters enable chronic storage and delivery without aggregation or device malfunction, making targeted delivery feasible
Solution Approach 2:
The composite formulation with phosphate or citrate buffers combined with carbohydrates creates a stable system that meets the stringent requirements of implantable devices. This formulation approach ensures compatibility with device materials, maintains stability during chronic storage, and enables reliable targeted delivery to reduce systemic side effects
Data Source
AI summary
A formulation for use in an implantable infusion device includes between about 5 mg/ml and about 500 mg/ml (e.g., about 10-25 mg/ml) of a TNF inhibitor polypeptide, 10 mM-25 mM of a phosphate or citrate buffer, has an ionic strength of the combined buffer and an optional salt of the equivalent of about 0.1-0.2 NaCl (e.g., about 0.15 M), 5% to 10% of a carbohydrate (e.g., trehalose or sucrose), has a pH of between 6 and 7, is fluid at room temperature and at 37° C., and has a viscosity of less than about 10 centipoise (e.g., between about 1 centipoise and 9 centipoise, between about 1 cp and about 5 cp, between about 1 cp and about 3 cp, or between about 1 cp and about 2.5 cp) at room temperature.